Somatic Mutation in Cerebral Cavernous Malformations

脑海绵状血管瘤的体细胞突变

• 批准号: 7530988
• 负责人: JUDITH Morse GAULT
• 金额: $ 20.21万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7530988
• 关键词: Abnormal Cell; Accounting; Address; Age; Blood; Blood Vessels; Brain; Brain hemorrhage; CCM1 gene; Cause of Death; Cavernous Malformation; Cell Line; Cells; Cerebrum; Clinical; Collection; Cystic kidney; DNA; Data; Disease; Dissection; Endothelial Cells; Epilepsy; Family; Formalin; Freezing; Future; Genes; Genetic Heterogeneity; Genotype; Germ-Line Mutation; Hemorrhage; Hereditary Disease; Heterogeneity; Individual; Investigation; Knock-out; Lasers; Lead; Lesion; Localized; Maps; Methods; Microscopic; Morus; Mutation; Mutation Analysis; Mutation Detection; Online Mendelian Inheritance In Man; Paraffin Embedding; Pathogenesis; Patients; Phenotype; Polycystic Kidney Diseases; Population; Proteins; Public Health; RNA; Rate; Reporting; Research; Research Personnel; Role; Sampling; Screening procedure; Sequence Analysis; Single-Stranded Conformational Polymorphism; Somatic Mutation; Spinal; Stroke; Symptoms; Technology; Testing; Tissue Sample; Tissues; United States; Vascular Endothelial Cell; base; brain tissue; cell type; disability; improved; innovation; lifetime risk; novel; success

DESCRIPTION (provided by applicant): Cerebral cavernous malformations (CCMs) occur in brain and spinal vasculature. Described as appearing like mulberries in blood vessels, they are found in 0.5% of the population and may cause hemorrhagic stroke and epilepsy. A "two-hit" mechanism has been proposed as a primary mechanism of CCM formation but has been difficult to prove. Consistent with a "two-hit" mechanism, patients with the sporadic nonheritable form of CCM generally have a single CCM; whereas, patients with a heritable form usually have multiple CCMs. A "two-hit" mechanism means that mutations knock-out both copies of a CCM gene in a cell that goes on to form the CCM lesion. Mutations in three genes, CCM1, CCM2 and CCM3 have been identified in heritable forms of CCM. If the "two-hit" mechanism was true, individuals with a germline mutation in a CCM gene would also have a somatic mutation specific to the CCM lesion. Likewise, patients with a sporadic form of CCM would have two somatic mutations in a cell type that makes up the CCM lesion. Several investigations failed to find somatic mutations in CCM lesions. However, the methods used were likely not sensitive enough. In addition only one of three CCM genes was screened. We have identified somatic and heritable germline mutations in two CCM lesions that map to the endothelial cells lining the caverns. Improved methods investigating the endothelial cells of the lesion will be employed. One aim with two projects is proposed to test the hypothesis that somatic mutations in the CCM1, CCM2 and CCM3 genes contribute to lesion genesis. The first project is to collect fresh frozen CCM lesions and characterize them into genetically distinguishable groups (sporadic non- heritable, heritable with known CCM1, 2 or 3 germline mutation and heritable without detectable germline mutation groups). The second project is to screen for CCM1, 2 and 3 somatic mutations in samples from sporadic cases and cases with known germline mutations. The proposed research is fundamental to understanding CCM pathogenesis. PUBLIC HEALTH RELEVANCE: Somatic mutations have been described as a major cryptic mechanism of common diseases because technologies that detect somatic mutations need to be developed. This proposal will develop new methods of somatic mutation detection and provide evidence of somatic mutation involvement in a common genetic disease, cerebral cavernous malformations, that predisposes to stroke and epilepsy.

描述（由申请人提供）：大脑和脊髓脉管系统中发生脑海绵状畸形（CCM）。被描述为像血管中的茂密的人一样，被发现在0.5％的人口中，可能导致出血性中风和癫痫病。已经提出了一种“两击”机制作为CCM形成的主要机制，但很难证明。与“两击”机制一致，偶发性不可遗忘的CCM的患者通常具有单个CCM。而具有遗传形式的患者通常具有多个CCM。一种“两击”的机制是指突变敲除一个细胞中CCM基因的两个副本，该副本继续形成CCM病变。在可遗传的CCM形式中已经鉴定出三个基因CCM1，CCM2和CCM3的突变。如果“两击”机制是正确的，则在CCM基因中具有种系突变的个体也将具有特定于CCM病变的体细胞突变。同样，具有零星形式的CCM形式的患者将在细胞类型中具有两个体细胞突变，构成CCM病变。几项调查未能在CCM病变中发现体细胞突变。但是，所使用的方法可能不够灵敏。另外，仅筛选了三个CCM基因中的一个。我们已经在两个CCM病变中鉴定出躯体和可遗传的种系突变，这些病变映射到洞穴内的内皮细胞。将采用改进研究病变内皮细胞的方法。提出了两个项目的一个目的，以检验CCM1，CCM2和CCM3基因中的体细胞突变有助于病变创世纪的假设。第一个项目是收集新鲜的冷冻CCM病变，并将其描述为具有遗传区分的组（零星的非遗传，可遗传的，具有已知的CCM1、2或3种系突变，而没有可检测的种系突变组）。第二个项目是在零星病例和已知种系突变病例的样品中筛选CCM1、2和3的体细胞突变。拟议的研究对于理解CCM发病机理至关重要。公共卫生相关性：已经将体突变描述为普通疾病的主要神秘机制，因为需要开发检测体突变的技术。该建议将开发新的躯体突变检测方法，并提供体细胞突变参与常见的遗传疾病，脑海绵状畸形，易于中风和癫痫病的证据。